The interaction of CD4 with class II MHC is essential for the cellular immune response, while the association of CD4 with the HIV envelope is an essential step in AIDS virus infection. An understanding of the molecular mechanisms involved in these two paradoxical processes form the basis for this proposal. Experiments are described to define the role of CD4 and CD8 in the selection events that accompany thymic development. The introduction of chimeric CD4 and CD8 genes into transgenic mice will permit an analysis of the intracellular signals generated when a thymocyte engages class I MHC, and how these signals differ upon engagement of class II molecules. A separate series of experiments are described to examine the precise molecular events by which CD4 mediates the association and entry of HIV with the target cell. Evidence is accumulating to suggest that molecules other than CD4 on the target cell may be required to facilitate efficient viral entry. We wish to isolate the genes encoding such factors in order to provide new insight into the mechanisms of entry of HIV beyond its initial association with CD4. This may also permit the construction of transgenic mice susceptible to HIV infection. Finally, CD4 may not serve as a passive attachment site for HIV, but may play an important role in the fusion events leading to virus entry. We have designed a series of experiments to ask whether CD4 is required solely to allow the close apposition of the virus in target cell membrane, or whether CD4 also plays an important role postbinding, facilitating the fusion and entry of HIV. Taken together, these genetic and biochemical experiments may ultimately permit a dissection of the molecular events leading to the fusion of HIV with the cell membrane.